Dimethyl fumarate (DMF) is an oral therapeutic agent which is reported to reduce the rejection often occurring in connection with organ transplantation (host versus graft reaction). Further, DMF is approved to be suitable as medicament for the treatment or prevention of a variety of diseases. For example, DMF is proposed in the treatment of autoimmune diseases such as multiple sclerosis. Further, DMF is suggested to be a suitable active pharmaceutical agent in the treatment of psoriasis. DMF is characterized by the following chemical Formula (1):

When taken orally DMF is reported to be hydrolyzed for example by the acidic ambience of the stomach or by esterases in the intestine to monomethyl fumarate (MMF). MMF can be regarded as a metabolite of DMF and can be characterized by the following chemical Formula (2):

The mechanisms of action of DMF or its metabolite MMF is reported to include inhibition of cytokine-induced nuclear translocation of the nuclear factor kappa B (NF-κB)), apoptosis of stimulated T cells, and increased production of the Th2 cytokines IL-4 and IL-5 in stimulated T cells, whereas generation of the Th1 cytokine interferon gamma (IFN-γ) is supposed to remain unaffected. DMF is described to activate the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2), which binds to antioxidant response elements in the promoters of protective genes such as NADPH-quinone-oxidoreductase-1 (NQO1) and heme-oxygenase-1. Thus, this ultimately raises the levels of the important intracellular antioxidant glutathione (cf. Albrecht P. et al., Journal of Neuroinflammation 2012, 9:163).
Further, it is alleged that the treatment of animals or primary cultures of CNS cells with DMF or MMF resulted in increased nuclear levels of active Nrf2, with subsequent up-regulation of canonical antioxidant target genes. DMF or MMF treatment increased cellular redox potential, glutathione, ATP levels, and mitochondrial membrane potential in a concentration-dependent manner. Treating astrocytes or neurons with DMF or MMF also significantly improved cell viability after toxic oxidative challenge in a concentration-dependent manner. This effect on viability was lost in cells that had eliminated or reduced Nrf2. These data suggest that DMF and MMF are cytoprotective for neurons and astrocytes against oxidative stress-induced cellular injury and loss, potentially via up-regulation of an Nrf2-dependent antioxidant response. Thus, in summary, it is indicated that in vivo DMF and MMF show about the same the efficacy, in particular on the transcription factor Nrf2.
As mentioned above, when taken orally DMF is rather rapidly hydrolyzed for example by the acidic ambience of the stomach or by esterases in the intestine to monomethyl fumarate (MMF). Thus, significant amounts of MMF are released within a short period of time. Such a rapid hydrolysis in principle was expected to provide a high level of MMF in the plasma within a short period of time.
However, it has been found that a high MMF plasma level might not be achievable. For example the organism might not be capable of transferring the small amount of MMF to the sites of the body where the pharmacological action takes place.
Additionally, it is reported that DMF has to be administered in quite high amounts and that the pharmaceutically active agent often shows undesirable side effects such as flush and especially symptoms related to the gastrointestinal tract such as irritation of the stomach and diarrhoea.
Consequently, there is still a need for new compounds, preferably for use as a medicament, more preferably in the treatment and/or prevention of systemic diseases, autoimmune diseases, and/or inflammatory diseases, for example multiple sclerosis and psoriasis. The medicaments should be capable of being applied in appropriate doses and should not cause significant undesired side effects.
Hence, it was an object of the present invention to overcome the drawbacks of the above-mentioned market drug substance DMF.
It was an object to develop a compound to be used as a medicament for the above-mentioned diseases wherein said compound shows advantageous pharmacokinetic properties.
Moreover, compounds should be provided which are hydrolysed to MMF more slowly than DMF in the human body (or under respective in-vitro conditions).
Further, the compounds should preferably cause few undesirable side effects.
Additionally, it was an object of the present invention to provide compounds which can be used in the treatment of the early phase of an autoimmune disease, in particular of multiple sclerosis, such that the progress of the disease can be delayed.